PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in U.S. women at all ages, and large knowledge gaps exist in CVD predictive and preventive strategies for women. The nuMoM2b Heart Health Study (nuMoM2b-HHS) has followed a demographically diverse cohort of 4,475 women enrolled and richly phenotyped during their first pregnancy, with data and biospecimens prospectively collected for up to 7 years thereafter. The overarching scientific goal of the nuMoM2b-HHS is to define the relationship between adverse pregnancy outcomes (APOs) and CVD to optimize CVD prediction, prevention, and treatment strategies for women. Continued follow-up of this cohort, building on a foundation of existing high-quality data, biospecimens, and administrative structures with a robust framework for ancillary study development and implementation, provides a unique opportunity to address knowledge gaps regarding the early mechanisms and trajectory of CVD in women. We propose to continue nuMoM2b-HHS follow-up through semiannual contacts and an in-person visit to assess CVD risk factors during grant years 3-5 (Aim 1). Accumulated longitudinal data and biospecimens will serve as a broadly accessible platform for ancillary studies to identify early mechanisms of CVD and to address additional NIH priority domains including early manifestations of cerebrovascular and renal disease in reproductive-age women. Ancillary studies (Aim 2) will expand data collection during the follow-up contacts and in-person visit, and add to the planned contact schedule, to permit the effective targeting of knowledge gaps required to optimize predictive and preventive strategies. The Specific Aims reflect a multifaceted approach to the study of the incidence and mechanisms of CVD development in women of reproductive age, focusing on the incidence of CVD risk factors in women with and without APOs (Aim 3); the associations between atherogenic phenotypes and sleep-disordered breathing during and after pregnancy and estimated CVD risk 6-15 years later (Aims 4 and 5, respectively); and identification of modifiable factors that influence or moderate these associations (Aim 6). This application has several strengths that reflect the potential for long-term success of the cohort: (1) The nuMoM2b-HHS will be led by three deeply experienced PIs with complementary domains of expertise in cardiology, maternal-fetal medicine, and biostatistics. (2) The network has robust infrastructure in place to maintain long-term participant engagement and support rigorous data collection. (3) The cohort's high-quality data and biospecimens have been collected under regulatory frameworks that support resource sharing and use in future research. (4) The network has established processes for successfully proposing, reviewing, and implementing ancillary studies. This foundation of strong leadership, robust administrative and operational infrastructure, and actualized long-term vision will provide an ideal environment for the nuMoM2b-HHS to continue to address critical knowledge gaps concerning CVD development in women of reproductive age.